the present invention relates to the use of angiotensin II (Ang II) or an analogue thereof, for the manufacture of a medicament for stimulating cilia, such as fallopian tube cilia and cilia on the secretory epithelia of the respiratory system. In particular, it relates to the use of Ang II, or an analogue thereof, for the manufacture of a medicament for stimulating cilia thus, for example, promoting ovarian transport, particularly in humans, with a consequential beneficial effect on conception. Alternatively, the medicament may be used for treating respiratory conditions such as asthma, bronchitis, or pneumonia.
Angiotensin II is an octapeptide, usually regarded as being produced in the blood, firstly by the action of renin, an enzyme secreted by the kidney, on angiotensinogen, resulting in the formation of the decapeptide precursor, angiotensin I, and secondly the action of a dipeptidase "angiotensin converting enzyme"; this enzyme acts on angiotensin I to form angiotensin II. Angiotensin II, in turn, undergoes hydrolysis by an aminopeptidase to yield the heptapeptide angiotensin III angiotensin 1-7).
The hormone angiotensin II (Ang II) forms part of the renin--angiotensin system which helps to control electrolyte balance and blood pressure within the body. There are several tissues within the body upon which Ang II acts, they include the adrenal gland, uterus, liver, brain and kidney.
Amongst the several established functions of angiotensin II, it is known to be involved in vaso-constriction, which leads to hypertension. Most treatments for high blood pressure will include blockage of angiotensin function in one way or another. Ang II also stimulates the secretion of aldosterone by the adrenal cortex. Aldosterone is a potent hormone which acts primarily on the kidney to promote sodium retention and thus inter alia, heightens the hypertensive effects of angiotensin acting directly on the vasculature.
Ang II is known to act on various sites in the brain, and one of its actions in animals is the regulation of thirst and drinking.
Angiotensin also has trophic effects on the vasculature, promoting growth of the muscles in the arterial wall. It is also thought to be angiogenic, i.e. it causes vascularisation of newly developing tissue.
Most of the established effects of Ang II have been found to occur via the AT.sub.1 subtype of the Ang II receptor, which is a seven transmembrane domain receptor. This receptor has been cloned and sequenced from a variety of tissues, and has been found to be a 359 amino acid polypeptide with a predicted molecular weight of around 40 kD (Berstein and Alexander, (1992), Endocr. Rev., 13, 381-386). Studies using photo-affinity labelling and crosslinking agents have suggested molecular weights for mature receptor of approximately 65 kD and 116 kD, respectively, which may reflectively, which may reflect glycosylation of asparagine residues within the extra-cellular domain.
From the recent development of a hybridoma cell line, see Barker, S., et al, J. Mol Endocr., 11, 241-245, (1993), it has been found possible to produce monoclonal antibodies to the AT.sub.1 subtype of the Ang II receptor. In consequence, such receptors have been found to exist both on maturing rat and human sperm tails, and on free swimming sperm obtained by vaginal lavage from mated rats, and in human ejaculated sperm.
WO (95/01202) discloses the use of angiotensin II to promote fertilization of mammalian eggs by increasing sperm motility. In particular, it discloses that Ang II may be used to promote in-vitro fertilization.
Although Ang II receptors have been extensively studied in the ovary and uterus, there is no information on their presence and role in the fallopian tube. Indeed, the AT1 subtype has been reported as absent from the uterus, although the AT2 subtype is present. Ang II have now been located in the human fallopian tube and uterus, using monoclonal antibodies to the AT1 subtype of the Ang II receptor. In the fallopian tube, and also in the tubules of the kidney, the respiratory tract, the intestine, breast ducts, prostate gland ducts, pancreatic duct, and in blood vessels, the antibody reveals that the receptor is specifically localised in the epithelial cells (endothelial cells in blood vessels), suggesting a role for the receptor in epithelial and ductal transport. In the fallopian tube, as in the respiratory tract, its distribution specifically shows close intimacy with the cilia which these epithelial cells carry, and that therefore ciliary function may be regulated by this receptor.
The incidence of chronic respiratory disease has shown a significant increase in recent years. There seems little doubt that much of this is associated with atmospheric pollution. Currently such chronic conditions are treated in a variety of palliative ways. Though generally valuable, few of these treatments directly address mucociliary clearance. This mechanism is a major natural defence system for the whole respiratory tract, which removes potentially harmful material through the co-ordinated beat of the cilia in a mucous blanket. Factors affecting the clearance rate therefore include the rheological properties of the mucous itself, as well as the beat frequency of the cilia. The means by which these properties are regulated under normal physiological conditions is largely unclear, though ciliary action is known to be affected by a number of factors. These include neurotransmitters and their agonists and antagonists, and the intracellular signal molecules, cyclic AMP, and calcium ions.